"Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased frisk of fracture. Bone strength reflects the integration of two main features: bone density and bone quality" [NIH consensus conference 2002]. Our underlying hypothesis is that alterations in mineral and matrix quantity and quality in addition to changes in micro-architecture and geometry account for the observed loss of bone strength in osteoporosis. Further we believe that these mineral and matrix parameters can be quantified by vibrational spectroscopy. The working hypothesis of this proposal is that broad distributions of mineral content, mineral crystal size, and collagen cross-links are present in healthy bone, that these distributions are absent in patients and animal models with osteoporosis, and that these distributions could be restored with the appropriate therapeutics. We will test the specific hypothesis that 1) the distribution of mineral crystallinity and collagen cross-links are related to whole bone strength and stiffness by evaluating how spectroscopically defined crystallinity and collagen cross-links (XLR) correlate with BMD (or T-score) in biopsies from patients with comparable BMD and the presence or absence of fractures, from femoral head samples from fracture and non-fracture cases, and in specimens with markedly increased crystallinity. We will also ask how crystallinity and XLR vary with micro-CT density and whole bone mechanical properties in ewes with different degrees of bone loss and how these parameters vary with elastic modulus in sex and age-matched primate osteons. We will then test the hypothesis that in treatment of osteoporosis, anabolic agents and not anti-resorptive drugs restore a broad distribution of mineral and collagen properties. Specifically we will examine how short-term treatment with alendronate or raloxifene alters bone mineral and matrix properties in a sheep model and how these effects agree wih those seen in representative human biopsies.